Double-Blind Comparison of the Efficacy and Safety of C213 to Placebo for the Acute Treatment of Cluster Headaches

This is a randomized, double-blinded, placebo-controlled study. Approximately 120 subjects who meet the entry criteria will be randomized 1:1:1 to receive one of three blinded treatments [C213 1.9 mg patch and placebo patch; C213 3.8 mg (1.9 mg x 2 patches), two placebo patches].

Qualified subjects will randomize to the double-blind treatment period at Day 1 and will have up to 48 weeks to confirm and treat a cluster headache. Using the eDiary to confirm they are experiencing a cluster headache, subjects will self-administer the patches and continue to respond to questions in the eDiary until 1-hour post treatment administration.

Inclusion criteria

• Able to provide written informed consent
• Women or men 18 to 65 years of age
• Greater than 1-year history of episodic or chronic cluster headache with onset prior to 50 years of age. Diagnosis must comply with ICHD-3 (International Headache Society (IHS) diagnostic criteria). Diagnostic criteria must include a history of at least 5 attacks not attributed to any other disorder that include all of the following criteria:

• Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 45-180 minutes (average, when untreated)
• Either or both of the following:

• At least one of the following symptoms or signs, ipsilateral to the pain:

• Conjunctival injection and/or lacrimation
• Nasal congestion and/or rhinorrhea
• Eyelid edema
• Forehead and facial sweating
• Miosis and or/ptosis
• A sense of restlessness or agitation
• Attacks have a frequency between one every other day and eight per day for more than half of the time when the disorder is active.
• Not better accounted for by another International Classification of Headache Disorders (ICHD) diagnosis
• Cluster history during the 12-month period prior to the screening visit must include:

• At least 1 cluster period
• Averaging 2-6 headaches per day
• Lasting at least 7 days
• Subject can distinguish cluster headaches from other headaches (i.e., migraine and tension-type headaches)
• Women of child-bearing potential must not be pregnant, must agree to avoid pregnancy during the trial, and must use one of the following or be surgically sterilized: intrauterine device, or a hormonal contraceptive
• Able to understand the operation of the electronic diary and able to apply the demo study drug patch correctly.

Exclusion criteria

• Contraindications to triptans
• Use of any prohibited concomitant medications within 30 days of screening
• History of hemiplegic migraine or migraine with brainstem aura
• Participation in another investigational trial within 30 days or 5 half-lives of investigational product (whichever is longer).
• Previous M207/C213 exposure in a clinical trial
• Subject has other significant pain problems that might confound the study assessments in the opinion of the investigator
• Diagnosis of any malignant disease (other than adequately treated or excised non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin) within the 5 years prior to screening
• History of unstable psychiatric illness requiring medication or hospitalization in the 12 months prior to study initiation
• Subjects who have a known allergy or sensitivity to zolmitriptan or its derivatives or formulations
• Subjects who have a known allergy or sensitivity to adhesions
• Subjects who have skin lesions or tattoos covering the entire potential area(s) of C213 application
• Woman who are pregnant, breast-feeding or plan a pregnancy during this study
• Clinically significant liver disease [Alanine Aminotransferase (ALT) > 150 U/L; Aspartate Aminotransferase (AST) > 130 U/L or bilirubin > 2x ULN]
• Clinically significant kidney disease (eGFR < 60 ml/min / 1.73 m² or to creatinine > 1.5 x ULN)
• Subject has clinically significant ECG findings, defined by:

• ischemic changes (defined as > 1mm of down-sloping ST segment depression in at least two contiguous leads)
• Q-waves in at least two contiguous leads
• clinically significant intra-ventricular conduction abnormalities (left bundle branch block or Wolf-Parkinson-White syndrome)
• clinically significant arrhythmias (e.g., current atrial fibrillation)
• History of coronary artery disease (CAD), coronary vasospasm (including Prinzmetal's angina), aortic aneurysm, peripheral vascular disease or other ischemic diseases (e.g., ischemic bowel syndrome or Raynaud's syndrome)
• Three or more of the following CAD risk factors:

• Current tobacco use
• Hypertension (systolic BP > 140 or diastolic BP > 90) or receiving anti-hypertensive medication for treatment of hypertension
• Hyperlipidemia - LDL > 159 mg/dL and/or HDL < 40 mg/dL (or on prescribed anti-cholesterol treatment)
• Family history of premature coronary artery disease (CAD) (< 55 years of age in male first-degree relatives or < 65 years of age in female first degree relatives)
• Diabetes mellitus
• History of cerebral vascular accident (CVA), transient ischemic attacks (TIA), or seizures
• History of concurrent illness that requires hospitalization within 30 days prior to study initiation
• Any other household member currently participating in a C213 study or relative of site staff member
• Any reason to believe that compliance with the study requirements and completion of evaluations required for this study will not be possible
• Any language barrier that, in the opinion of the Investigator, would preclude communication and compliance with the study requirements
• History or current abuse of or dependence on alcohol or drugs that would interfere with the results or adherence to study requirements
• Any positive drug screens for phencyclidine (PCP), 3,4-methylenedioxy-methamphetamine (MDMA) (ecstasy), cocaine, and/or meth/amphetamine(s)
• Current or planned use of hallucinogens (e.g. psilocybin) during the trial
• Any clinically relevant abnormal findings in the physical exam, vital signs or laboratory tests that, in the opinion of the Investigator, may put the subject at risk